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Oncologic Drugs Advisory Committee February 27, 2002

Issues in the Clinical Development of Investigational Agents Being Evaluated for the Post-surgical Adjuvant Treatment of High-Risk (Stage IIb and III) Melanoma. Oncologic Drugs Advisory Committee February 27, 2002. Adjuvant Treatment for Malignant Melanoma Outline of Presentation.

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Oncologic Drugs Advisory Committee February 27, 2002

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  1. Issues in the Clinical Development of Investigational Agents Being Evaluated for the Post-surgical Adjuvant Treatment of High-Risk (Stage IIb and III) Melanoma Oncologic Drugs Advisory Committee February 27, 2002

  2. Adjuvant Treatment for Malignant MelanomaOutline of Presentation • Survey of biological products being studied under IND for treatment of melanoma • Basis for approval of INTRON-A for adjuvant treatment of melanoma • Overview of randomized controlled trials with adjuvant IFN alpha in melanoma • Comparison of effect size to other adjuvant treatment

  3. Adjuvant Treatment for Malignant MelanomaOutline of PresentationInvited Speakers • John M. Kirkwood, MD Efficacy and Safety of High-Dose IFN-2b in Patients With High-Risk Resected Cutaneous Melanoma M. Kirkwood, MD • Joseph Ibrahim, PhD Cure Rate Models and Adjuvant Trial Design for ECOG Melanoma Studies in the Past, Present, and Future

  4. Adjuvant Treatment for Malignant MelanomaRegulatory considerations 21 CFR 312.42 (b)(1)(I): FDA may place an ongoing or proposed investigation on hold if it finds that “Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury”

  5. Adjuvant Treatment for Malignant MelanomaEvolution in Regulatory Approach • Based on results of E1684 and E1690, enrollment of subjects with stage IIb and III disease in studies under IND was permitted due to absence of clear effect on survival • Following the results of E1694 as well as other published literature, evidence of the effect on survival was strengthened

  6. Adjuvant Treatment for Malignant MelanomaEvolution in Regulatory Approach • Enrollment of subjects in trials of investigational agents was restricted for patients with Stage IIb and III disease to • Subjects medically unable to tolerate Intron A at the approved dose and schedule • Subjects with a prolonged interval between surgical resection and adjuvant therapy ( 6 months) • Recurrence on or following Intron A

  7. Adjuvant Treatment for Malignant Melanoma Investigational Agents Being Evaluated for the Treatmentof Melanoma

  8. Adjuvant Treatment for Malignant MelanomaSurvey Approach • CBER database reviewed for INDs submitted for cancer treatment between 1975 - 2000 • Of the 2,665 applications 196 (7%) were for treatment of melanoma • Annual reports were assessed to identify the number of studies conducted and subjects accrued • Analysis of IND activity by product category

  9. Adjuvant Treatment for Malignant MelanomaNumber of INDs for the Treatment of Melanoma 96 100 80 72 60 Number of INDs 40 18 20 5 3 0 1975-1980 1981-1985 1986-1990 1991-1995 1996-2000

  10. Adjuvant Treatment for Malignant MelanomaNumber of Studies and Subjects Accrued by Phase of Study

  11. Adjuvant Treatment for Malignant MelanomaInvestigational Products • Tumor vaccines • Gene transfer products • Monoclonal antibodies • Cytokines • Cellular therapies

  12. Adjuvant Treatment for Malignant MelanomaInvestigational Products 60 40 Percent of INDs 20 0 Vaccines Gene Transfer Monoclonal Antibodies Cytokines Cellular Therapies Products

  13. Adjuvant Treatment for Malignant MelanomaInvestigational Products • Tumor vaccines • Tumor cell vaccines • Peptide vaccines • Antigens presented by dendritic cells • Tumor cell lysates or fragments

  14. Adjuvant Treatment for Malignant Melanoma Basis for Approval of INTRON-A and Supplemental Data Reviewed by FDA

  15. Adjuvant Treatment for Malignant Melanoma Study ECOG 1684 • Efficacy Supplement filed February 1995 • Data presented at ODAC July 1995 • Approval December 1995

  16. Adjuvant Treatment for Malignant Melanoma Study ECOG 1684 Histological Diagnosis Surgical Excision and Regional LN Dissection Randomization Interferon a2b No Treatment N= 143 N= 137 Interferon alpha 2b 20 MIU/m2 IV 5x/wk x 4 wk then 10 MIU/m2 SC 3x/wk x 11 mo

  17. Adjuvant Treatment for Malignant Melanoma Study ECOG 1684 • Improvement in median RFS 9 months (1.72 vs 0.98 years p=0.009) • Improvement in median OS 12 months (3.8 vs 2.8 years p=0.06)

  18. Adjuvant Treatment for Malignant Melanoma K-M estimates of DFS ECOG 1684(from the published report) Interferon a2b No treatment

  19. Adjuvant Treatment for Malignant Melanoma K-M estimates of OS ECOG 1684(from the published report) Interferon a2b No treatment

  20. Adjuvant Treatment for Malignant Melanoma Labeled Indication • “INTRONA Interferon alfa-2b, recombinant for Injection is indicated as adjuvant to surgical treatment in patients 18 years of age or older with malignant melanoma who are free of disease but at high risk for systemic recurrence within 56 days of surgery.”

  21. Adjuvant Treatment for Malignant MelanomaStudy ECOG 1690 Histological Diagnosis Surgical excision Randomization Interferon a2b High Dose Interferon a2b Low Dose No Treatment 215 215 140 HIGH DOSE: 20 MIU/m2 IV 5x/wk x 4 wk then 10 MIU/m2 SC 3x/wk x 11 mo LOW DOSE: 3 MIU SC 3x/wk x 2 yr

  22. Adjuvant Treatment for Malignant Melanoma K-M estimates of DFSECOG 1690(from the published report) Interferon a2b high dose Interferon a2b low dose No treatment

  23. IFN a2b high dose IFN a2b low dose No treatment Adjuvant Treatment for Malignant Melanoma K-M estimates of OS ECOG 1690(from the published report)

  24. Adjuvant Treatment for Malignant Melanoma K-M Estimates of 3-year RFS and OS Studies E 1684 and E1690 (high dose)

  25. Adjuvant Treatment for Malignant Melanoma Interferon a 2b Adverse Events • Non-serious adverse events are common • Serious adverse events are uncommon (<2%) • Adverse events are reversible with dose modification and/or medical management

  26. Adjuvant Treatment for Malignant Melanoma Interferon a 2b Adverse Events Serious Adverse events • Liver failure • Depression with suicidal ideation • Retinopathy

  27. Adjuvant Treatment for Malignant MelanomaUse of INTRON-A in high risk melanoma Estimates for 2001

  28. Adjuvant Treatment for Malignant Melanoma An Overview of the Published Literature Jawahar Tiwari PhD

  29. Adjuvant Treatment for Malignant MelanomaCriteria for Inclusion • Randomized trials • All observational concurrent controlled trials • Adjuvant treatment

  30. Adjuvant Treatment for Malignant MelanomaSearch Methodology Database searched (Jan 1990 Dec 2001) MEDLINE, EMBASE, BIOSIS, LIFE SCIENCES, DERWENT, CANCERLIT, Cochrane Controlled Clinical Trials, Cochrane Database of Systemic Reviews

  31. Adjuvant Treatment for Malignant Melanoma Analytic Approach • Individual patient data from FDA files • Summary data from published reports • Additional information from investigators • Estimates of odds (O - E) method • KM estimates of survival at 3 years

  32. Adjuvant Treatment for Malignant Melanoma INTRON-A High Dose

  33. Adjuvant Treatment for Malignant Melanoma K-M estimates of DFS and OS ECOG 1694(from the published report) Interferon a2b Interferon a2b GMK vaccine GMK vaccine DFS OS

  34. Adjuvant Treatment for Malignant Melanoma INTRON-ALow Dose

  35. Adjuvant Treatment for Malignant Melanoma Rusciani et al. 1997 (from the published report) • Recurrence rates at 3 year • Control 30% (N=70) • Interferon a 2b 13% (N=84) • Difference 17% (95% CI: 4% to 30%)

  36. Adjuvant Treatment for Malignant Melanoma K-M estimate of DFSand OSScottish Melanoma Group(from the published report) Interferon a2b Interferon a2b No treatment No treatment DFS OS

  37. Adjuvant Treatment for Malignant MelanomaROFERON-AHigh Dose and Low Dose

  38. Adjuvant Treatment for Malignant Melanoma K-M estimate of DFS and OSNCCTG 83-7052(from the published report) Interferon a 2a Interferon a 2a No treatment No treatment DFS OS

  39. Adjuvant Treatment for Malignant Melanoma K-M estimate of DFSWHO CT 16(from the published report) Interferon a2a Interferon a2a No treatment No treatment DFS OS

  40. Adjuvant Treatment for Malignant Melanoma K-M estimate of DFSM 23031(from the published report) Interferon a2a Interferon a2a No treatment No treatment DFS OS

  41. Adjuvant Treatment for Malignant Melanoma K-M estimate of DFSAustrian Melanoma Cooperative Group (from the published report) Interferon a2a No treatment

  42. Adjuvant Treatment for Malignant Melanoma Odds Ratio for Relapse Kirkwood (1996) Kirkwood (2000) 1690L Kirkwood (2000) 1690H Cameron (2000) Kirkwood (2001) Creagan (1995) Pehamberger (1998) Grob (1998) Cascinelli (2001) All studies (N=3536) 0.4 1 1.6 0.2 2

  43. Adjuvant Treatment for Malignant Melanoma Odds Ratio for Survival Kirkwood (1996) Kirkwood (2000) 1690L Kirkwood (2000) 1690H Cameron (2000) Kirkwood (2001) Creagan (1995) Pehamberger (1998) Grob (1998) Cascinelli (2001) All studies (N=3536) 0.2 0.4 1 1.6 2

  44. Adjuvant Treatment for Malignant MelanomaWheatley et. al. Meta-Analysis • Data from 10 studies • Largely based on published reports • Includes : • EORTC 18871 and 18952 • UKCCCR • Does not include ECOG 1694 • Approximately 3700 patients

  45. Adjuvant Treatment for Malignant Melanoma Overview by FDA and Wheatley FDA DFS Wheatley DFS FDA OS Wheatley OS 0.2 0.4 1 1.6 2

  46. Adjuvant Treatment for Malignant Melanoma Overview Effect of IFN on 3-year survival 8-9 % absolute improvement in relapse-free survival 4-5% absolute improvement in overall survival

  47. Adjuvant Treatment for Malignant Melanoma Summary • Clinically important and convincing evidence of reduction in relapse  20% reduction in relapse rate; P< 0.0001 • Evidence of improved survival 10% reduction in death rate; P<0.065

  48. Adjuvant Treatment for Malignant Melanoma Effect Size Adjuvant TreatmentRelativeReduction in the Odds of Recurrence and Death

  49. C B R E

  50. Adjuvant Treatment for Malignant Melanoma K-M estimates of DFS ECOG 1694(from the published report) Interferon a2b GMK vaccine

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